Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that protein production and mRNA expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and IL-3 are decreased in activated mononuclear cells (MNC) from human umbilical cord compared with adult peripheral blood. Reduced production of these colony-stimulating factors (CSF) during states of increased demand, as occurs during overwhelming bacterial infection, may play a role in the pathogenesis of neutropenia and thrombocytopenia in the newborn. To determine whether the reduced mRNA expression and CSF production from activated cord MNC is secondary to the decreased transcriptional activity of the corresponding genes, we determined the transcriptional rate of GM-CSF, G-CSF, IL-3, and M-CSF by nuclear run-on assays. Cord and adult MNC were isolated by Ficoll-Hypaque density centrifugation. A total of 10(8) MNC from cord and adult blood were stimulated as follows: GM-CSF and G-CSF [32 nmol/L phorbol-12-myristate-6-acetate (20 micrograms/L) + 2 mg/L phytohemagglutinin for 6 h]; IL-3 [32 nmol/L phorbol-12-myristate-6-acetate (20 micrograms/L) + 0.5 mumol/L A 23187 for 6 h]; and macrophage CSF (2 micrograms/L recombinant human GM-CSF for 24 h). The nuclei from unstimulated and stimulated cells were isolated and labeled with 32P-uridine triphosphate. Newly elongated 32P-labeled RNA transcripts were hybridized to slot blots of CSF DNA. To minimize cross hybridization artifacts, short fragments (0.5-1.0 kb) of cDNA were used.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transcriptional rates of granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, interleukin-3, and macrophage colony-stimulating factor genes in activated cord versus adult mononuclear cells: alteration in cytokine expression may be secondary to posttranscriptional instability. 750 24

Irinotecan (CPT-11 [Camptosar]), a semisynthetic derivative of the plant alkaloid camptothecin, is bioactivated by carboxylesterases (EC3.1.1-) to the topoisomerase I inhibitor SN-38, a minor metabolite. Bioactivation of intravenously administered irinotecan by carboxylesterases occurs predominantly in the liver. Two human carboxylesterase isoforms responsible for SN-38 formation have been characterized. At relevant hepatic irinotecan concentrations up to 12 micrograms/mL, a low-Km isoform is responsible for irinotecan bioactivation. High concentrations of drugs commonly coadministered with irinotecan do not inhibit carboxylesterase activity. Intestinal carboxylesterases can also generate SN-38, followed by subsequent oral absorption. A second major polar metabolite of irinotecan, aminopentanecarboxylic acid (APC), is the product of CYP3A4-mediated oxidation of the terminal piperidine ring. APC is 100-fold less active than SN-38 as a topoisomerase I inhibitor and is a relatively weak inhibitor of acetylcholinesterase. SN-38 is eliminated mainly through conjugation by hepatic uridine glucuronosyltransferase (UGT*1.1), the same isoezyme responsible for glucuronidation of bilirubin. Grade 4 irinotecan-related toxicity (ie, neutropenia, diarrhea) has recently been reported in two patients with deficient UGT*1.1 activity. SN-38 glucuronide (SN-38G), which has only 1/100th the antitumor activity of SN-38, is actively secreted into the bile by a canalicular multispecific organic anion transporter. Deconjugation of SN-38G to SN-38 by beta-glucuronidase produced by the intestinal flora may contribute to enterohepatic recirculation of SN-38 and delayed intestinal toxicity.
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PMID:Pharmacology of irinotecan. 972 89

Leukocyte apoptosis is an energy-dependent process that facilitates resolution of the cellular inflammatory response. Levels of apoptosis can be accelerated or inhibited after exposure to various stimuli. To compare apoptosis in transmigrated leukocytes, two models of peritonitis in mice were used that both cause leukocyte influx into the peritoneal cavity: (1) intraperitoneal thioglycollate administration producing a sterile peritonitis and (2) cecal ligation and puncture (CLP) producing a polymicrobial bacterial peritonitis. Samples of blood and peritoneal exudate cells (PEC) were collected at multiple time points after induction of peritonitis. Leukocytes were either fixed immediately to determine an immediate apoptosis level or cultured for 24 h to determine a delayed apoptosis level. Apoptosis was assessed using terminal uridine-triphosphate nick-end labeling (TUNEL) assay, flow cytometry, and confocal microscopy. Leukocyte influx into the peritoneal cavity was confirmed in both models. At all time points, and in both models, there was increased immediate apoptosis in PEC compared with unmanipulated controls and this increase was maximal in CLP after 18 h, although it appeared to remain at a stable level in the sterile peritonitis model by 3 h. There was also an increase in PEC delayed apoptosis at early time points in both models, again maximal at 18 h for CLP, with the levels being significantly higher than the thioglycollate model at 6 h and 18 h. The mice had a relative peripheral neutropenia at 6 h after CLP, but not post thioglycollate injection, and this persisted until 42 h. Lung and liver MPO levels were elevated in CLP but did not increase after thioglycollate. There was no increase in immediate peripheral leukocyte apoptosis in either model, but an increase in delayed peripheral leukocyte apoptosis was observed by 18 h in both models. Peripheral leukocyte CD1lb expression, which is a marker of activation, was also persistently elevated in the CLP model, but not in sterile peritonitis. In conclusion, CLP is a more potent stimulus for apoptosis of leukocytes than their migration to the site of inflammation alone, as occurs in the thioglycollate model. Blood leukocyte apoptosis also appears not to be dependent on CD11b expression, and therefore activation status.
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PMID:Immediate and delayed leukocyte apoptosis in two models of peritonitis. 1183 42

SN-38 is the active metabolite of irinotecan and it is metabolised through conjugation by uridine diphosphate glucuronosyl transferase (UGT1A1). The major toxicity of irinotecan therapy is diarrhoea, which has been related to the enzymatic activity of UGT1A1. We examined the influence of the UGT1A1 gene promoter polymorphism in the toxicity profile, in the response rate and in the overall survival (OS) in 95 patients with metastatic colorectal cancer treated with an irinotecan-containing chemotherapy. Genotypes were determined by analysing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Clinical parameters and genotypes were compared by univariate and multivariate statistical methods. The more frequent adverse effects were asthenia (34 patients), diarrhoea (29 patients) and neutropenia (20 patients). Severe diarrhoea was observed in 7/10 homozygous (70%) and 15/45 heterozygous (33%) in comparison to 7/40 (17%) wild-type patients (P=0.005). These results maintained the statistical significance in logistic regression analysis (P=0.01) after adjustment for other clinical relevant variables. The presence of severe haematological toxicity increased from wild-type patients to UGT1A1(*)28 homozygotes, but without achieving statistical significance. No relationship was found between the UGT1A1(*)28 genotypes and infection, nausea or mucositis. In univariate studies, patients with the UGT1A1(*)28 polymorphism showed a trend to a poorer OS (P=0.09). In the multivariate analysis, the genotype was not related to clinical response or to OS. The role of the UGT1A1 genotype as a predictor of toxicity in cancer patients receiving irinotecan demands the performance of a randomized trial to ascertain whether genotype-adjusted dosages of the drug can help to establish safe and effective doses not only for patients with the UGT1A1(*)28 homozygous genotype but also for those with the most common UGT1A1 6/6 or 6/7 genotype.
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PMID:UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. 1528 Sep 27

Drug-metabolizing enzymes are responsible for the activation or detoxification of cytotoxic drugs. Allelic variants are present with a variable frequency in different populations around the world and have an important role in the therapeutic index of such drugs. It is known that polymorphisms in thiopurine methyltransferase and dihydropyrimidine dehydrogenase have been associated with altered drug metabolism and increased risk of severe toxicity from 6-mercaptopurine and 5-fluorouracil, respectively. Additionally, a variant number of dinucleotide-repeat sequences in the promotor for uridine 5'-diphosphate glucuronosyltransferase 1A1 influences the glucuronidation of SN-38, the active metabolite of irinotecan, which is associated with severe toxicity, including diarrhea and neutropenia. In the same way, polymorphisms in thymidylate synthase have been associated with pyrimidine-associated toxicity and also with response to chemotherapy. The examples shown in this review demonstrate the usefulness of pre-screening patients for well-characterized polymorphism to identify the best-tolerated and most-effective treatment.
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PMID:Genetic determinants of cancer drug efficacy and toxicity: practical considerations and perspectives. 1616 69

In the treatment of advanced colorectal cancer, irinotecan has become one of the most important drugs, despite its sometimes unpredictable adverse effects. To understand why some patients experience severe adverse effects (diarrhea and neutropenia), while others do not, the metabolic pathways of this drug have to be unraveled in detail. Individual variation in expression of several phase I and phase II metabolizing enzymes and ABC-transporters involved in irinotecan metabolism and excretion, at least partly explains the observed pharmacokinetic interpatient variability. Although the difference in expression-level of these proteins to a certain amount is explained by physiologic and environmental factors, the presence of specific genetic determinants also does influence their expression and function. In this review, the role of genetic polymorphisms in the main enzyme-systems (carboxylesterase, cytochrome P450 3A, and uridine diphosphate-glucuronosyltransferase) and ABC-transporters (ABCB1, ABCC2, and ABCG2) involved in irinotecan metabolism, are discussed. Since at this moment the field of pharmacogenetics and pharmacogenomics is rapidly expanding and simultaneously more rapid and cost-effective screening methods are emerging, a wealth of future data is expected to enrich our knowledge of the genetic basis of irinotecan metabolism. Eventually, this may help to truly individualize the dosing of this (and other) anti-cancer agent(s), using a personal genetic profile of the most relevant enzymes for every patient.
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PMID:Role of pharmacogenetics in irinotecan therapy. 1634 44

From February, 2001 to September, 2002, the Southwest Oncology Group (SWOG) accrued 65 patients with advanced gastric adenocarcinoma to a phase II trial of weekly 5-FU, leucovorin, and the orally-administered uridine analog PN401. Of these 65 patients, 57 were assessable for survival and toxicity, which were the endpoints for the study. Treatment consisted of the administration of 1200 mg/m(2) of 5-FU, 500 mg/m(2) of leucovorin, and 6 grams of PN401 every 8 h, beginning 8 h after the completion of the 5-FU infusion, and continuing for a total of 8 doses (48 grams) during each weekly chemotherapy session. Therapy was delivered for six weeks out of every 8-week treatment cycle. The gastrointestinal toxicity of this regimen was mild with 2 patients experiencing grade 3 stomatitis, and 6 patients having grade 3 diarrhea; and the hematologic toxicity was acceptable with 6 of 57 patients found to have had grade 3 or 4 leukopenia, and 14 of 57 patients experiencing grade 3 or 4 neutropenia. There were two deaths judged possibly related to treatment; one in a patient who experienced a variety of Grade 2 gastrointestinal toxicities and died at home with an unknown cause of death; and a second patient who also died at home, and for whom treatment-related sepsis could not be ruled out. The overall median survival was 7.2 months. The ability to safely deliver twice the usual dose of 5-FU with leucovorin on a weekly schedule suggests that oral uridine analog supplementation with PN401 may enhance the therapeutic index of the fluoropyrimidines.
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PMID:Phase II trial of PN401, 5-FU, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach: a Southwest Oncology Group study. 1683 2

The primary end point of the study was the analysis of associations between polymorphisms with putative influence on 5-fluorouracil/irinotecan activity and progression-free survival (PFS) of patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Peripheral blood samples from 146 prospectively enrolled patients were used for genotyping polymorphisms in thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), excision repair cross-complementation group-1 (ERCC 1) xeroderma pigmentosum group-D (XPD), X-ray cross-complementing-1 (XRCC 1), X-ray cross-complementing-3 (XRCC 3) and uridine diphosphate-glucuronosyltransferases-A1 (UGT1 A1). TS 3'-UTR 6+/6+ and XRCC3-241 C/C genotypes were associated with adverse PFS. Hazard ratio for PFS achieved 2.89 (95% confidence interval=1.56-5.80; P=0.002) in 30 patients (20%) with both risk genotypes. Risk for Grade III-IV neutropenia was significantly associated with UGT1A1*28 7/7 genotype. These promising findings deserve further investigations and their validation in independent prospective studies.
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PMID:Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. 1754 67

The hepatic isoform 1A1 of uridine diphosphate glucuronosyltransferase is responsible for glucuronidation and detoxification of SN-38, the active metabolite of irinotecan. The presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter leads to a significant decrease in SN-38 glucuronidation. Patients with the UGT1A1 (TA)7 allele are more likely to experience severe neutropenia and diarrhea following irinotecan chemotherapy. We assessed the distribution of the UGT1A1 (TA)n polymorphism in healthy male and female US residents of European and Asian descent. We used a fluorescent polymerase chain reaction-based assay to detect UGT1A1 (TA)n polymorphisms in 138 healthy volunteers (56 Caucasians, 37 Chinese, 37 Filipino and eight Japanese) between the ages of 18 and 65 years. The chi-test was used to assess between-group differences in the distribution of UGT1A1 (TA)n genotypes. The UGT1A1 (TA)6/6 genotype was significantly more common in Asians than in Caucasians (76 vs. 46%), whereas the (TA)6/7 (39 vs. 20%) and (TA)7/7 (13 vs. 5%) genotypes were more common in Caucasians than in Asians. Genotype distributions did not differ significantly between men and women in either group. The UGT1A1 (TA)5/5 genotype was detected in one Caucasian woman. In conclusion, consistent with previous reports, the UGT1A1 (TA)7/7 genotype was significantly more common in Caucasians than in Asians. UGT1A1 (TA)n/n genotype distribution did not vary with sex in individuals of European or Asian descent.
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PMID:Distribution of the UGT1A1*28 polymorphism in Caucasian and Asian populations in the US: a genomic analysis of 138 healthy individuals. 1776 98

Pharmacogenetic research indicates a relationship between a polymorphism in the gene encoding uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and irinotecan inactivation, in that degradation of SN-38, the active metabolite of irinotecan, correlates inversely with the number of TA repeats in the TATA element of the UGT1A1 promoter region. Individuals who are homozygous for the UGT1A1*28 allele (7 repeats) may exhibit reduced degradation of SN-38 and increased probability of severe toxicities. Clinical study results, as reported in the literature, have not been uniform, however, in showing a relation between genotype and the development of toxicities. Even when correlations are statistically significant, confidence intervals are wide, rendering assessment of individual risk difficult at best. Irinotecan labeling recommends testing for the UGT1A1*28 allele and reducing irinotecan dosing in patients who are positive to reduce the likelihood of dose-limiting neutropenia only, but not diarrhea. Importantly, both dose-limiting neutropenia and diarrhea are dependent on numerous known and unknown factors, such as the specific regimen used, duration of therapy, doses, cycle of treatment, and complexities of irinotecan pharmacodynamics and pharmacokinetics, including other key enzymes and drug transporters. Guidance on how to modify irinotecan dosing or how to incorporate the impact of multiple variables into clinical decision-making does not exist. Furthermore, pharmacogenomic test results at this time can only provide an estimate of risk for subsets of populations rather than a risk-benefit estimate for an individual. Consequently, these test results are supplementary to clinical judgment, which requires assessing multiple variables that contribute to phenotype to arrive at individual dosing decisions.
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PMID:Irinotecan and uridine diphosphate glucuronosyltransferase 1A1 pharmacogenetics: to test or not to test, that is the question. 1872 Mar 61


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